tbuckley/cabot-search huggingface dataset:
Abstract 1452: Big data analysis revealed signalling activity and key regulators in human prostate cancer cell lines
Authors: Siyuan Cheng, Lin Li, Xiuping Yu
Journal: Cancer Research (2023)

Abstract Background: Human prostate cancer (PCa) cell lines are the most used models for research. The commonly used PCa cell lines can be roughly categorized into 3 groups: androgen receptor (AR)+, neuroendocrine (NE)+ and double negative (AR- NE-) cell lines. However, although these cell lines have been extensively used in PCa research since their establishment decades ago, a global molecular characterization of these cell lines is still lacking, especially in the aspect of cell signaling activity and their clinical relevance, which requires a large scale of data mining. Methods: The RNA-seq, DNA-seq and proteomic datasets were gathered from public cohort and our lab’s collection. From these data, a PCa cell line multi-omics database (PCMD) was established. Single sample gene set enrichment analysis (ssGSEA) was used to reveal the signaling pathways enriched in each PCa cell line. Additionally, human PCa patient single cell RNAseq data-based deconvolution and human PCa patient bulk RNAseq data-based nearest-neighbor (NN) graph analysis were used to evaluate the clinical relevance of each PCa cell line. The DNA-seq, ATAC-seq, DNase HS-seq and Bisulfite-seq datasets were used to annotate the key genes. Results: The PCMD database was established by compiling more than 1000 RNASeq datasets derived from various PCa cell lines. The important signaling pathways and transcription factors were revealed for each PCa cell line. Further, the cell lines were annotated with relative clinical stages. Additionally, an interactive webApp was established for scientists to explore and visualize PCMD data. Conclusion: our research characterized PCa cell lines using unbiased strategies and large sample number. It is our hope that this study would aid researchers to develop hypothesis and choose appropriate cell line to use. Funding: This study is supported by: Feist-Weiller Cancer Center, LSU Health Shreveport. Citation Format: Siyuan Cheng, Lin Li, Xiuping Yu. Big data analysis revealed signalling activity and key regulators in human prostate cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1452.
Abstract 6764: Multi-parametric comparison of scRNA-seq with CITE-seq and ultrahigh-plex spatial phenotyping of proteins in FFPE head and neck tumor biopsies: An opportunity to generate uniquely comprehensive multi-omic single cell datasets to investigate the tumor microenvironment
Authors: Aditya Pratapa, Shawn M. Jensen, Niyati Jhaveri, Yoshinobu Koguchi, Venkatesh Rajamanickam, Brady Bernard, Tanisha Christie, Brian Piening, Rom S. Leidner, Oliver Braubach, Bernard A. Fox
Journal: Cancer Research (2023)

Abstract Single cell RNA-seq (scRNA-seq) performed on cell suspensions isolated from tumor biopsies provides substantial insights into the transcriptional state of the cells in the tumor microenvironment (TME). Complementing this work with multi-omic Cellular Indexing of Transcriptomes and Epitopes (CITE-seq), which adds barcoded antibodies to label the surface of isolated cells, allows us to additionally characterize surface proteins. While information gleaned from these studies is dramatically expanding our understanding of the evolving immune response and tumor-immune interactions, it lacks an appreciation of the many spatial relationships that are present within the TME. Spatial phenotyping with the power of single cell resolution and whole slide imaging provides a valuable tool for identifying the cellular architecture and organization of spatial neighborhoods that perform critical roles in tumor progression, resistance, and clinical responses. Here, we explore bioinformatic strategies aimed at combining scRNA-seq and CITE-seq data with single-cell spatial protein data obtained with the PhenoCycler-Fusion (PCF) imaging platform. To this end, we performed whole-slide spatial phenotyping with an ultrahigh-plex PCF panel on FFPE human head and neck tumors. The same biopsies were also enzymatically digested and subjected to CITE-seq and scRNA-seq analysis. The combined multi-omic, single cell dataset provides a uniquely comprehensive account of the cellular states, functional significance and spatial neighborhoods that govern the TME. This study represents a novel approach to integrate high dimensional data from bulk tissue and single-cell spatial technologies to provide deeper insights into tumor biology and, in turn, to develop more informed strategies for combination immunotherapy trials and improved patient outcomes. Citation Format: Aditya Pratapa, Shawn M. Jensen, Niyati Jhaveri, Yoshinobu Koguchi, Venkatesh Rajamanickam, Brady Bernard, Tanisha Christie, Brian Piening, Rom S. Leidner, Oliver Braubach, Bernard A. Fox. Multi-parametric comparison of scRNA-seq with CITE-seq and ultrahigh-plex spatial phenotyping of proteins in FFPE head and neck tumor biopsies: An opportunity to generate uniquely comprehensive multi-omic single cell datasets to investigate the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6764.
Abstract 4963: Heme Sequestration as an effective strategy for the suppression of tumor growth and progression of SCLC
Authors: Adnin Ashrafi, Narges Salamat, Eranda Berisha, Parinaz Sadat Alemi, Maria Del Carmen Chacon Castro, Zakia Akter, Li Zhang
Journal: Cancer Research (2023)

Abstract Small-cell lung cancer (SCLC) accounts for 15% of all lung cancers with exceptionally high proliferative rate, early metastasis, and poor prognosis. Chemotherapy has provided SCLC patients considerable survival benefits over the past three decades. Etoposide-platinum (EP) is the preferred first-line regimen. SCLC is initially highly responsive to cisplatin and etoposide chemotherapy, but in almost every case becomes rapidly chemo resistant. Despite attempts to improve outcomes utilizing multiple different strategies, drug resistance remains a major obstacle in clinical consequences of patients with SCLC. Recent research aims to elucidate mechanisms of resistance to improve drug response and treatment outcomes. Our lab has shown that limiting heme via inhibition of heme uptake using heme sequestering peptide (HeSP2) can delay growth and progression of NSCLC tumors. This HeSP2 can also effectively inhibit angiogenesis, normalize tumor vasculature, and alleviate tumor hypoxia in NSCLC tumors and thereby inhibit lung tumor advancement. Here we aim to determine if HeSP2 can be used to enhance the therapeutic efficacy of traditional chemotherapy in the treatment of SCLC. Our preliminary results show that HeSP2 can effectively reduce cell proliferation of SCLC cells like H889 and H720. To understand the mechanism by which the heme sequestering protein limit tumor development, we generated human SCLC H889 xenograft lung tumor model in NOD/SCID mice subcutaneously. Mice were treated with saline (control), HeSP2 alone, cisplatin-etoposide, and HeSP2-cisplatin-etoposide in combination. Tumor growth was monitored using caliper measurements. Tumors tissues were harvested, processed and paraffin embedded for immunohistochemistry (IHC) and histology experiments. The results imply that heme sequestration can be a potential strategy for suppressing small cell lung cancer tumor progression and improve survival outcome of patients. Citation Format: Adnin Ashrafi, Narges Salamat, Eranda Berisha, Parinaz Sadat Alemi, Maria Del Carmen Chacon Castro, Zakia Akter, Li Zhang. Heme Sequestration as an effective strategy for the suppression of tumor growth and progression of SCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4963.
Abstract 4721: Yin Yang 1-induced long non-coding RNA DUXAP9 drives oral squamous cell carcinoma by blocking CDK1-mediated EZH2 degradation
Authors: Wei Cao, Wenkai Zhou
Journal: Cancer Research (2023)

Abstract Background: lncRNAs play a critical role in oral squamous cell carcinoma (OSCC) progression and metastasis. However, the detailed molecular mechanism is not fully understood. Methods: Differential-expressed lncRNAs between OSCCs and paired adjacent tissues were identified by microarray. The expression of lncRNADUXAP9 (DUXAP9) was detected by RNAscope and quantitative real-time PCR (qRT-PCR). The gain-of-function and loss-of-function of DUXAP9 were evaluated in vitro and in vivo assays. Chromatin immunoprecipitation (ChIP)and luciferase assays were performed to analyze the transcriptional regulation of DUXAP9. RNA pull-down assays, LS-MS/MS analysis, RNA immunoprecipitation assays, and Co-immunoprecipitation (Co-IP) were performed to address the molecular mechanism through which DUXAP9promotes OSCC progression. Results: By analyzing lncRNA microarray data, we identified a novel nuclear-localized DUXAP9, which is upregulated in OSCC. The high level of DUXAP9is positively associated with lymph-node metastasis, poor pathological differentiation, advanced clinical stage, worse overall survival, and worse disease-specific survival in OSCC patients. DUXAP9 significantly promotes cell proliferation, migration/invasion, and metastasis in vitro and in vivo through an EZH2-dependent manner. Yin Yang 1(YY1) was found to activate the transcriptional expression of DUXAP9 in OSCC. Furthermore, DUXAP9was proven to physically interact with EZH2 and inhibit EZH2 degradation via the suppression of the phosphorylation of EZH2, thereby blocking EZH2nucleus to cytoplasm translocation. Conclusions: Here we demonstrated a novel mechanism mediated by lncRNA DUXAP9 at the posttranslational level, which contributes to OSCC progression, thus providing a promising target for OSCC therapy. Keywords: LncRNA DUXAP9, YY1, EZH2, Ubiquitination, Oral squamous cell carcinoma Citation Format: Wei Cao, Wenkai Zhou. Yin Yang 1-induced long non-coding RNA DUXAP9 drives oral squamous cell carcinoma by blocking CDK1-mediated EZH2 degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4721.
Abstract 423: β-Escin eradicates cancer stem-like population in HER2-positive breast cancer with trastuzumab resistance
Authors: Soeun Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Eunsun Jung, Yong koo Kang, Seojin Jang, So Ra Seock, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo, Jaeyoun Park
Journal: Cancer Research (2023)

Abstract Purpose: Trastuzumab resistance is a multifactorial phenomenon arising from the steric effects of p95HER2, activation of HER2 downstream signaling pathways, and the existence of cancer stem cells. We sought to examine the capacity of β-escin, an anti-inflammatory drug, to address trastuzumab resistance in HER2-positive breast cancer cells. Experimental designs: The effects of β-escin in trastuzumab-sensitive and -resistant cell lines were evaluated for apoptosis, HER2 expression, calpain activation and CSC-like properties. In vivo trastuzumab-resistant xenograft mice model was used to examine tumor growth, angiogenesis and organ toxicity of β-escin. Results: β-escin induced mitochondrial-mediated apoptosis accompanied by reactive oxygen species (ROS) production and increased active p18Bax fragmentation, leading to caspase-3/-7 activation. β-escin downregulated p95HER2, HER2 and HER3 as well as their phosphorylation. β-escin-induced HER2 degradation appears to be mediated by calpain activation. We observed that treatment with β-escin induced cleavage of HER2 and p95HER2 (at 75, 50 and 42 kDa fragments) in HER2 overexpressing MDA-MB-231 cells. Attenuation of CSC-related features by β-escin challenge was accompanied by marked reductions in CD44high/CD24low stem-like cells and aldehyde dehydrogenase 1 (ALDH1) activity as well as hindrance of mammosphere formation. β-escin administration also significantly retarded tumor growth and angiogenesis in a trastuzumab-resistant JIMT-1 xenograft model via downregulation of CSC-associated markers and intracellular domain HER2. Importantly, β-escin selectively inhibited malignant cells and was less toxic to normal mammary cells, and no toxic effects were found in liver and kidney function in animals. Conclusion: Herein, for the first time, we report the potent efficacy of β-escin, a drug repurposing candidate with an exceptional safety profile in addressing trastuzumab-resistant HER2-positive breast cancer. Citation Format: Soeun Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Eunsun Jung, Yong koo Kang, Seojin Jang, So Ra Seock, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo, Jaeyoun Park. β-Escin eradicates cancer stem-like population in HER2-positive breast cancer with trastuzumab resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 423.
Abstract 3403: Leveraging a p53 “super-tumor suppressor” to understand mechanisms of lung adenocarcinoma regression
Authors: Mengxiong Wang, Alyssa Kaiser, Kathryn Bieging-Rolett, Colleen Brady, Laura Attardi
Journal: Cancer Research (2023)

Abstract Lung cancer is the leading cause of cancer deaths worldwide, and lung adenocarcinoma (LUAD) comprises the majority of lung cancer cases. Inactivation of the TP53 tumor suppressor gene, which encodes the p53 transcription factor, is observed in ~50% of human LUADs and is associated with poor prognosis and therapeutic responses. Hence, pharmacological restoration of p53 is an appealing strategy for LUAD treatment. Previous studies have demonstrated that p53 reactivation in mouse LUAD models leads to tumor regression. Here, we seek to understand the molecular mechanisms through which p53 restoration promotes tumor regression. To this end, we sought to better understand the transcriptional programs underlying tumor regression by leveraging an allelic series of transcriptional activation domain (TAD) mutants. We generated mouse models of LUAD initiated by oncogenic Kras and loss of p53, followed by reactivation of wild-type p53 or p53 TAD mutants, including the TAD1 (p5325,26), TAD2 (p5353,54), and TAD1/2 (p5325,26,53,54) mutants. We find that restoration of wild-type p53 induces significant regression of established tumors. Interestingly, we find that restoration of the p5353,54 mutant induces tumor regression even more potently than wild-type p53, reminiscent of our previous findings showing this mutant is a “super” tumor suppressor in pancreatic cancer. In contrast, the transcriptionally-dead TAD1/2 mutant, p5325,26,53,54, is unable to drive tumor regression. To understand the basis of tumor suppression, we are currently analyzing antiproliferative cellular responses in tumors, including cell cycle arrest, apoptosis, autophagy and differentiation. We have also developed a complementary in vitro system to further explore the molecular mechanisms of p53 action in LUAD regression. RNA-sequencing analysis in this system has revealed transcriptional programs underlying the enhanced tumor regression with the p5353,54 mutant. Collectively, these findings have illuminated the individual contributions of each p53 TAD to LUAD regression. In particular, elucidating the mechanisms by which the “super” tumor suppressor p5353,54 mutant induces tumor regression will provide great insight for developing therapeutic strategies to restore and amplify p53 function. Citation Format: Mengxiong Wang, Alyssa Kaiser, Kathryn Bieging-Rolett, Colleen Brady, Laura Attardi. Leveraging a p53 “super-tumor suppressor” to understand mechanisms of lung adenocarcinoma regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3403.
Abstract 4724: Single cell multiomic profiling of high-grade serous carcinoma
Authors: Leticia Assad Maia Sandoval, Wazim Mohammed Ismail, Amelia Mazzone, Amik Munankarmy, Jagneet Kaur, Tsering Tashi, Xiaonan Hou, Nagarajan Kannan, Ann Oberg, Scott H. Kaufmann, Saravut John Weroha, Alexandre Gaspar-Maia
Journal: Cancer Research (2023)

Abstract Ovarian cancer is one of the most common gynecologic malignancies, with high-grade serous carcinoma (HGSC) as the most frequent and deadliest type of ovarian cancer (OC). With the recent advances in cancer epigenomic profiling, it has become clear that intra-tumor heterogeneity driven by genetic and epigenetic factors may be the basis of resistance, where current treatments could efficiently target sub-populations of cells while a sub-group may be resistant, or prone to develop resistance. With epigenomic profiling and single cell sequencing technology, we aim to characterize cell signatures that translate as prognostic markers and novel drug targets. We have mapped the epigenomic landscape of HGSC in 12 patient-derived xenografts (PDX), and their metastatic counterparts (circulating tumor cells and ascites present in the PDX models) using an assay for transposase-accessible chromatin (or ATAC-seq) and compared it with normal fallopian tube organoids to identify tumor and metastatic-specific regulatory elements. We also performed RNA-seq to validate potential transcriptional dependencies associated with resistance to chemotherapy. In order to identify potentially chemotherapy-resistant subpopulations and further validate the activity of some of the transcription factors that can be driving resistance, we performed single cell multiomic profiling using the 10x Multiome sequencing platform (scRNA+scATAC from the same nuclei) in HGSC patient samples and PDX. Finally, we performed immunohistochemistry of patient tissue slides for target markers and correlated it with overall survival in OC patients. As previously suggested, a subset of cancer clonal cells can drive treatment resistance and metastasis and result in poor patient outcomes. Data derived from PDX ATAC-seq showed a cancer stem cell signature driven by SOX2 in metastatic samples compared to the paired PDX primary tumor, suggesting a role for SOX2 in disease progression. Interestingly, SOX2 expression in epithelial cells in the Multiome analysis is more patient-specific than other stem cell markers, like CD133. We also observed that SOX2 expression negatively correlated with prognosis. These data, taken together, point out the promising role of SOX2 as a prognostic and targetable marker for HGSC. Citation Format: Leticia Assad Maia Sandoval, Wazim Mohammed Ismail, Amelia Mazzone, Amik Munankarmy, Jagneet Kaur, Tsering Tashi, Xiaonan Hou, Nagarajan Kannan, Ann Oberg, Scott H. Kaufmann, Saravut John Weroha, Alexandre Gaspar-Maia. Single cell multiomic profiling of high-grade serous carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4724.
Abstract 3878: Targeting Hippo-YAP, BRD4 and RAS-MAPK interplay in lung cancer to forestall drug resistance
Authors: Nilanjana Chatterjee, Victor Olivas, Wei Wu, Ben Powell, Trever Bivona
Journal: Cancer Research (2023)

Abstract Introduction: Identifying parallel survival pathways or compensatory mechanisms that limit the response to targeted therapy is critical to discover effective combinatorial strategies for the treatment of lung cancer and to prevent emergence of drug resistance Results: Using combination drug screening in a panel of cell line models of non-small cell lung cancer (NSCLC), we identified the tumor suppressor STK11 (aka LKB1) as a molecular biomarker of sensitivity to BET and RAS-MAPK pathway inhibitors combination in NSCLC. We found a small molecule inhibitor of BET (bromodomain and extra terminal) family proteins (BRD4, 3, 2), PLX51107, suppressed BRAF and KRAS mutant NSCLC cell proliferation and in combination with RAS (KRAS G12C), RAF or MEK inhibitor led to pronounced loss in cell viability with potent MYC downregulation and synergistic apoptosis induction in vitro and potent tumor regression or stasis in vivo in several KRAS mutant CDX and PDX mouse models of NSCLC. However, BRAF and KRAS mutant NSCLC cells with co-occurring mutations in STK11 were resistant to BET and RAS, RAF or MEK co-inhibition. To unravel the underlying mechanism of resistance to BET and RAS-MAPK inhibitors upon STK11 loss we modeled STK11 deficiency in BRAF and KRAS mutant NSCLC cells and tumors. We found that STK11 loss creates an unprecedented dependence on YAP/TEAD TFs. STK11 silencing in BRAF and KRAS mutant NSCLC cells resulted in nuclear transfer/activation of the HIPPO pathway effector, YAP, upregulation of the YAP target BIRC5 (aka Survivin) and rescued the synthetic lethality due to BET and RAS, RAF or MEK co-inhibition. Phenocopying STK11 loss, constitutively active YAP (YAP5SA), but not transcriptionally inactive YAP (YAPS94A), mitigated the deleterious effects of BET and RAS, RAF or MEK co-suppression in BRAF and KRAS mutant NSCLC cells with potent upregulation of the pro-survival factor BIRC5. Conversely, we found that co-silencing YAP or TEADs with BETs re-sensitized BRAF and KRAS mutant NSCLC cells with co-occurring mutations in STK11 to BET and RAS-MAPK inhibitors combination and caused synthetic lethality. Conclusion: This study uncovered a functional interaction between BET proteins, STK11, HIPPO-YAP and RAS-MAPK signaling pathways in lung cancer. These results will help identify combinatorial strategies for treating aberrant RAS-MAPK pathway driven lung cancer more effectively and forestall drug resistance. Citation Format: Nilanjana Chatterjee, Victor Olivas, Wei Wu, Ben Powell, Trever Bivona. Targeting Hippo-YAP, BRD4 and RAS-MAPK interplay in lung cancer to forestall drug resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3878.